How does ethanol alter opioid tolerance?

酒精饮料中消费的乙醇经常被发现与海洛因或美沙酮一起出现在阿片类药物过量死亡中。因此，确定乙醇可能如何与阿片类药物相互作用，以增加其非法使用的危险，是极其重要的。我们自己的工作有证据表明，急性暴露于低剂量乙醇会降低对呼吸抑制剂的耐受性和吗啡的止痛作用，而长期摄入酒精似乎会降低阿片类药物的止痛效果。这表明，乙醇影响阿片类药物作用的方式可能有所不同，这取决于乙醇消费的性质(间歇性摄入与慢性摄入)。因此，这项研究的目的是在分子、细胞和行为水平上确定急性和慢性乙醇注射如何改变对阿片类药物呼吸抑制作用的耐受水平，阿片类药物呼吸抑制作用是过量服用阿片类药物最重要的生理后果。我们将寻求在分子和细胞水平上阐明阿片类药物呼吸抑制作用耐受性形成的信号机制，然后确定乙醇如何影响这些机制。不同的阿片类药物被认为通过不同的细胞机制诱导耐受，这增加了乙醇可能不同地影响对不同阿片类药物的耐受的可能性。为此，我们将研究在阿片成瘾治疗中非法使用的一系列阿片类药物是如何产生耐受性的，并确定急性和慢性给予乙醇对每种药物耐受性的影响。我们将结合对呼吸的整体动物研究和大脑中控制呼吸的神经元的电生理记录，以及对阿片类药物信号和耐受的重要中介的体外分子研究。我们的实验结果将为阿片成瘾者联合使用酒精和阿片类药物的危险提供重要的新信息，并提供科学证据，以适当、重要的公共卫生信息为基础。

Ethanol, consumed in alcoholic beverages, is frequently found to be present along with heroin or methadone in opioid overdose fatalities. It is therefore extremely important to determine exactly how ethanol may be interacting with opioid drugs to enhance the dangers of their illicit use. There is evidence from our own work to suggest that acute exposure to low doses of ethanol can reduce tolerance to the respiratory depressant and analgesic actions of morphine whereas chronic ethanol consumption appears to reduce the analgesic effectiveness of opioid drugs. This suggests that there may be differences in the way ethanol affects the actions of opioids depending upon the nature of ethanol consumption (intermittent v chronic intake). The aim of the research described in this proposal is therefore to determine at the molecular, cellular and behavioural levels how acute and chronic ethanol administration can alter the level of tolerance to the respiratory depressant effects of opioids - the most important physiological consequence of taking these drug in relation to death in overdose.We will seek to elucidate at the molecular and cellular levels the signaling mechanisms underlying the development of tolerance to the respiratory depressant actions of opioid drugs and then determine how these can be affected by ethanol. Different opioid drugs are thought to induce tolerance by distinct cellular mechanisms raising the possibility that ethanol could differentially affect tolerance to different opioid drugs. For this reason we will study how tolerance develops to a range of opioids that are used illicitly and in the therapy of opioid addiction and determine the effects of acute and chronic administration of ethanol on the tolerance to each drug. We will combine whole animal studies of respiration with electrophysiological recording from neurones in the brain that control respiration and in vitro molecular studies of important mediators of opioid signaling and tolerance. The results from our experiments will provide important new information on the dangers of the combined use of alcohol and opioids by opioid addicts and provide scientific evidence on which appropriate, important public health messages can be based.